Chapter B8 - Motor Complications in Primate Models of Parkinson Disease

Abstract

Chronic levodopa treatment of Parkinson's disease (PD) patients ultimately produces motor response complications (MRCs) that include response fluctuations and dyskinesias. Recent nonhuman primate studies suggest that MRCs from the pulsatile nonphysiological stimulation of dopaminergic receptors on striatal spiny neurons increase the sensitivity of corticostriatal glutamatergic synaptic transmission. Changes to the glutamatergic signaling pathways and adenosinergic and serotonergic pathways both intrinsic and extrinsic to the striatal dopaminoceptive medium-spiny neurons may also contribute to the pathogenesis of motor dysfunction in advanced PD. Because of these alterations, basal ganglia output the changes in ways that favor the appearance of Parkinsonian signs and motor complications. While MRCs associated with chronic levodopa therapy are a major cause of treatment failure, the biochemical mechanisms underlying this phenomenon remain yet unclear. Based on recent behavioral and pharmacological data, the pathogenesis of PD motor complications in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primates may be influenced by increased synaptic efficacy of corticostriatal glutamatergic synaptic transmission associated with changes in medium spiny neuron signaling pathways. In addition to delivery systems that provide more continuous and physiological dopaminergic receptor stimulation, future goals of primate research in MRCs should include developing pharmacological agents that normalize striatal glutamatergic dysfunction by interacting with striatal N-methyl-D-aspartate and amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptors or other surface receptors. The MPTP-lesioned nonhuman primate, therefore, serves as an invaluable tool for discovering more novel and salutary treatment approaches to attenuate levodopa-induced motor complications and to prevent a loss of its therapeutic efficacy during the course of the disease.